Stem Cell Dysfunction in Aging-Related Diseases

Citation: Stem Cell Therapies in Clinical Trials: Progress and Challenges. Trounson, Alan et al. Cell Stem Cell, Volume 17, Issue 1, pages 11–22.

Pluripotent stem cells are known for their exceptional self-renewal capacity and their ability to differentiate into various cell types. Increasing evidence suggests that the aging process negatively impacts stem cells. As stem cells age, their regenerative ability declines, and their capacity to differentiate into different cell types diminishes. This reduction in stem cell function due to aging is believed to contribute significantly to the pathophysiology of many age-related diseases. Understanding how the aging process affects stem cell function is crucial not only for grasping the mechanisms behind aging-related diseases but also for developing effective stem cell-based therapies for future age-related conditions. This review explores the basis of stem cell dysfunction in various aging-related diseases and discusses potential treatments under development to address stem cell deficiencies caused by aging.Citation: World J Exp Med. 2017 Feb 20; 7(1): 1–10. "Effect of aging on stem cells." Abu Shufian Ishtiaq Ahmed, et al.

Regenerative medicine is advancing towards clinical applications using stem cell and progenitor cell therapies to repair damaged organs. The liver and pancreas, both derived from the endodermal stem cell population, share biliary stem cells located in the biliary trunk (hBTSC), which serve as precursors for hepatic stem/progenitor cells in the herring canal and as progenitor cells for the pancreatic duct. These cells mature along the radial axis within the bile duct wall, as well as along the proximal-distal axis, beginning at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have explored the effects of stem cell transplantation into the hepatic arteries of patients with various liver diseases, using liver stem/progenitor cells from fetal livers. Immunosuppression was not required. In contrast, all control subjects either died within a year or experienced liver function decline. However, subjects transplanted with 100-150 million liver stem/progenitor cells showed improvements in liver function and survival for several years. The safety and efficacy of these transplantations are still being evaluated. While stem cell therapy for diabetes using hBTSC is under investigation, further preclinical studies are necessary before clinical applications. Additionally, mesenchymal stem cells (MSC) and hematopoietic stem cells (HSC) are being used to treat patients with chronic liver disease or diabetes. MSCs have proven effective through the paracrine release of trophic factors and immune regulators, but their ability to differentiate into mature parenchymal cells or pancreatic islet cells is limited. The impact of HSC is mainly attributed to immune system regulation.

Stem Cells. 2013 Oct;31(10):2047-60. doi: 10.1002/stem.1457. "Concise review: clinical programs of stem cell therapies for liver and pancreas." Lanzoni G1, Oikawa T

The recovery effect mediated by stem cell transplantation occurs through two main pathways: one involves the secretion of angiogenic factors and cytokines, while the other involves the transplantation and differentiation of stem cells into tissue-specific cells. Stem cells can enhance the local secretion and expression of angiogenic factors and cytokines, aiding in the reconstruction of the microcirculatory system, improving blood flow, and enhancing islet β-cell function, which helps alleviate diabetic peripheral artery disease (PAD). Additionally, stem cells can differentiate into endothelial cells, promoting the recovery of endothelial cell dysfunction. These effects may be influenced by miRNA and extracellular vesicles (MEX).

Diabetic wound healing through MSC grafting occurs via three main pathways: first, through angiogenesis and the secretion of factors and cytokines; second, by regulating the immune system; and third, by transplanting and differentiating into tissue-specific cells. Stem cells can enhance the local secretion and expression of angiogenic factors and cytokines, contributing to the improvement of diabetic peripheral artery disease (PAD) and diabetes. Additionally, stem cells regulate the activity of T cells, natural killer cells, macrophages, and dendritic cells, helping to inhibit infections and inflammatory responses. MSCs can also differentiate into target tissues, facilitating repair. These effects may be associated with miRNA and extracellular vesicles (MEX).

The recovery effects of stem cell transplantation occur through two primary pathways: the secretion of angiogenic factors, cytokines, and neurotrophic factors, and the transplantation and differentiation into tissue-specific cells. Stem cells can enhance the local secretion and expression of angiogenic factors and cytokines, aiding in the improvement of diabetic peripheral artery disease (PAD) and diabetes, which leads to the alleviation of diabetic neuropathy. Neurotrophic factors also help restore nerve fiber function and improve nerve conduction. Additionally, stem cells can differentiate into target tissues, promoting repair.

Above: Representative micro-computed tomography images of the kidney segment show an improved microvascular structure in atherosclerotic renal artery stenosis (ARAS) pigs that underwent percutaneous transluminal renal angioplasty (PTRA), with an adrenal infusion of adipose tissue-derived MSCs performed 4 weeks earlier. Below: Trichrome staining of kidney tissue shows reduced fibrosis in the ARAS + PTRA + MSC-treated pigs (×40, blue).

Clinical application of MSCs in diabetes:Stem cell transplantation has shown promise as a safe and effective treatment for patients with diabetes mellitus (DM). Among various trials, the best outcomes were observed with D34+ hematopoietic stem cell (HSC) therapy for type 1 diabetes (T1DM), while the worst results were seen with human umbilical cord blood (HUCB) therapy for T1DM, where diabetic ketoacidosis hindered the therapeutic effect.

A line graph depicting changes in C-peptide and HbA1c levels at baseline, 3 months, 6 months, and 12 months following stem cell treatment in type 1 diabetes (T1DM) patients. Data are presented as mean ± SEM, with **** indicating P < 0.0001.

(E-F) T2D patients received UCB and BM-MNC injections into the pancreas (n = 3 and n = 107), while UC-MSC and PD-MSC were injected intravenously (n = 22 and n = 10, respectively). A line graph illustrating changes in C-peptide and HbA1c levels at baseline, 3 months, 6 months, and 12 months post-treatment.

Citation: PLoS One. 2016 Apr 13;11(4)

. Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis. El-Badawy A, El-Badri N.

Nat Commun. 2012 Apr 17;3:784. doi: 10.1038/ncomms1784.
Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches.
Toyoshima KE, Asakawa K, Ishibashi N, Toki H, Ogawa M, Hasegawa T, Irié T, Tachikawa T, Sato A, Takeda A, Tsuji T.

Overview
Organ replacement regenerative medicine is expected to enable the replacement of organs damaged by disease, injury, or aging in the near future. This study demonstrates complete organ regeneration through bioengineered bone and intradermal transplantation of spore germ. The blastoderm and ovule are reconstituted using embryonic skin-derived cells and adult stem cell region-derived cells, respectively. Bioengineered hair follicles develop with proper structure and form functional connections with surrounding host tissues, such as the epidermis, hind limb muscle, and nerve fibers. These bioengineered hair follicles also exhibit hair cycles and hair formation, which are restored through the reorganization of hair follicle stem cells and their niches. This research highlights the potential of using adult tissue-derived hair follicle stem cells for biotechnological organ replacement therapy.

(a) Schematic of the procedure for creating and transplanting bioengineered hair follicle embryos.(b) Phase contrast images of dorsal skin, tissues, dissociated single cells, and bioengineered hair follicle embryos from mouse embryos, reconstructed using the organ germ method with nylon thread (arrowhead). Scale bar: 200 μm.(c) Histological analysis of isolated tentacles from adult mice. Macroscopic and H&E staining of bristles are shown in the left two panels. The dashed red line in both macroscopic observation (left) and H&E staining (right) indicates the interface of the bulge and SB regions. The boxed area in the left panel, stained with H&E, shows the bulge and SB areas, highlighted in the higher magnification panel. The bulge region was immunostained with anti-CD49f (red, left) and anti-CD34 (red, middle) antibodies, and Hoechst 33258 dye (blue). The black dashed line in the high magnification H&E image marks the interface of the follicular epithelium. IF = funnel, RW = annular body, half of the hair follicle. Scale bar: 100 μm.(d) Histological and ALP analysis of initial regeneration in the tactile valve area and DP cells. Hair bulbs (left two images) and cultured DP cells (right two images) were analyzed using ALP enzyme staining. The red dotted line indicates Auber’s line. Scale bar: 100 μm.(e) Longitudinal section of bioengineered hair during eruption and growth, mediated by the inter-epithelial tissue-interlocking plastic device (guided). Corresponding images show cystogenesis in bioengineered hair follicles on day 14 post-transplantation (without guide). H&E staining on days 0, 3, and 14 post-transplantation is shown at the bottom. Scale bar: 100 μm.(f) Wound healing immediately after implantation (left), day 3 (center), and the ejection of hair shafts on days 14 and 37. Macrostructural observation of hair growth during the development of bioengineered hair follicles, including growth on the chest (upper) and spleen (lower). Scale bar: 1.0 mm.

(a) Histological and immunohistochemical analysis of bioengineered hair (upper) and tentacular (central) vesicles. The boxed area in the low magnification H&E panel is shown at higher magnification in the right panel. Arrows indicate sebaceous glands. Scale bar: 100 μm. Bioengineered hair follicles were immunostained with anti-versican (lower left) and α-SMA (arrowhead, lower right) antibodies, and enzymatically stained for ALP (lower center). Scale bar: 50 μm.(b) Bioengineered human hair produced through transplantation of biologically treated hair follicle embryos, reconstituted with intact dermal papilla (DP) from bulge-derived epithelial cells and human scalp follicles. Human hair formed by bioengineering was photographed on day 21 after transplantation and analyzed by H&E staining. The right panel shows species identification of bioengineered hair follicles based on nuclear morphological characteristics. The inset area is shown at higher magnification. Scale bar: microscope 500 μm, H&E 100 μm, nuclear dyeing 20 μm.(c) Dense intradermal transplantation of bioengineered follicular pathogens. A total of 28 independent bioengineered hair follicle germs were transplanted into the uterine cervical skin of a mouse, showing high-density hair growth on day 21 after transplantation. Scale bar: 5 mm.

Bioengineered hairs and tentacles were integrated with various tissues, including nerve fibers, retractor muscles, and striated muscles derived from either host or donor cells. The bioengineered hair was associated with smooth muscle due to the regeneration of the NPNT-expressing bulge region, resembling the natural structure. However, neither NPNT expression nor smooth muscle attachment was observed in the bulge region of the bioengineered hair.

Source: Toyoshima, K., Asakawa, K., Ishibashi, N., Toki, H., Ogawa, M., Hasegawa, T., Irié, T., Tachikawa, T., Sato, A., Takeda, A., & Tsuji, T. (2012). Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nature Communications, 3, 784. https://doi.org/10.1038/ncomms1784

A schematic illustrating the induction, differentiation, and application of stem cells for Parkinson's disease (PD) research and therapy. Stem cells can be categorized into four groups—ESCs, NSCs, MSCs, and iPSCs—each with progressively decreasing totipotency. (1) ESCs, primarily derived from the blastocyst, have the ability to differentiate into all three germ layers (endoderm, mesoderm, ectoderm) under normal conditions. ESCs can also be induced to differentiate into NSCs and MSCs. (2) NSCs, isolated from specific brain niches or reprogrammed from fibroblasts, are capable of differentiating into neural lineages, including neurons and nearly all glial cells. (3) MSCs, mainly sourced from mesenchymal tissue, can differentiate into almost all mesodermal-derived cells. Remarkably, MSCs can also be induced to become dopaminergic (DA) neurons under specific induction protocols. (4) iPSCs, reprogrammed from adult human somatic cells (e.g., fibroblasts) by introducing OSKM factors (Oct 3/4, Sox 2, Klf 4, and c-Myc), represent a promising stem cell source. Based on Good Manufacturing Practice (GMP) standards, these stem cells and their terminally differentiated derivatives can be further sorted, purified, and expanded for various applications, including disease modeling, drug screening, and clinical regenerative therapy (CRT). For instance, ESCs, MSCs, NSCs, and DA neurons are used in the preparation of PD models, drug screening, and CRT treatments for PD.

Source: Shen, Y., Huang, J. (2016). A Compendium of Preparation and Application of Stem Cells in Parkinson’s Disease: Current Status and Future Prospects. Frontiers in Aging Neuroscience. 31 May 2016.